Pharmacology of montelukast sodium (Singulair™), a potent and selective leukotriene D4receptor antagonist Journal Articles uri icon

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  • Montelukast sodium (Singulair™), also known as MK-0476 (1-(((1(R)-(3-(2-(7-chloro-2-quinolinyl)-(E)-ethenyl)phenyl)(3-2-(1-hydroxy-1-methylethyl)phenyl)propyl)thio)methyl)cyclopropane) acetic acid sodium salt, is a potent and selective inhibitor of [3H]leukotriene D4specific binding in guinea pig lung (Ki0.18 ± 0.03 nM), sheep lung (Ki4 nM), and dimethylsulfoxide-differentiated U937 cell plasma membrane preparations (Ki0.52 ± 0.23 nM), but it was essentially inactive versus [3H]leukotriene C4specific binding in dimethylsulfoxide-differentiated U937 cell membranes (IC5010 μM) and [3H]leukotriene B4specific binding in THP-1 cell membranes (IC5040 μM). Montelukast also inhibited specific binding of [3H]leukotriene D4to guinea pig lung in the presence of human serum albumin, human plasma, and squirrel monkey plasma with Kivalues of 0.21 ± 0.08, 0.19 ± 0.02, and 0.26 ± 0.02 nM, respectively. Functionally, montelukast antagonized contractions of guinea pig trachea induced by leukotriene D4(pA2value 9.3; slope 0.8). In contrast, montelukast (16 μM) failed to antagonize contractions of guinea pig trachea induced by leukotriene C4(45 mM serine–borate), serotonin, acetylcholine, histamine, prostaglandin D2, or U-44069. Intravenous montelukast antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. leukotriene D4but did not block bronchoconstriction to arachidonic acid, histamine, serotonin, or acetylcholine. Oral administration of montelukast blocked leukotriene D4induced bronchoconstriction in conscious squirrel monkeys, ovalbumin-induced bronchoconstriction in conscious sensitized rats (ED500.03 ± 0.001 mg/kg; 4 h pretreatment), and also ascaris-induced early and late phase bronchoconstriction in conscious squirrel monkeys (0.03–0.1 mg/kg; 4 h pretreatment). A continuous i.v. infusion of montelukast (8 μg∙kg−1∙min−1) resulted in a 70% decrease in the peak early response and a 75% reduction of the late response to ascaris aerosol in allergic conscious sheep. Montelukast, a potent and selective leukotriene D4receptor antagonist with excellent in vivo activity is currently in clinical development for the treatment of asthma and related diseases.Key words: montelukast, MK-0476, Singulair™, leukotriene D4receptor antagonist, airway smooth muscle, antigen challenge.


  • Jones, TR
  • Labelle, M
  • Belley, M
  • Champion, E
  • Charette, L
  • Evans, J
  • Ford-Hutchinson, AW
  • Gauthier, J-Y
  • Lord, A
  • Masson, P
  • McAuliffe, M
  • McFarlane, CS
  • Metters, KM
  • Pickett, C
  • Piechuta, H
  • Rochette, C
  • Rodger, Ian
  • Sawyer, N
  • Yoyng, RN
  • Zamboni, R
  • Abraham, WM

publication date

  • February 1, 1995

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